Sulfonyl urea and carbamate ACAT inhibitors

ABSTRACT

A pharmaceutically useful compound which lowers blood cholesterol levels having the formula wherein X is oxygen or -NH-; Ar is phenyl, substituted phenyl, naphthyl or substituted naphthyl; R1 is hydrogen, lower alkyl or benzyl; and R2 is a straight or branched alkyl group having from 5 to 17 carbon atoms which may be substituted on the 1-carbon position with methyl, ethyl, phenyl, or substituted phenyl, or a cycloalkyl group having from 3 to 8 carbon atoms.

This is a continuation of U.S. application Ser. No. 07/776,112 filedOct. 15, 1991, now U.S. Pat. No. 5,254,589.

BACKGROUND OF THE INVENTION

The present invention describes a series of novel sulfonyl ureas andcarbamates which inhibit acyl-CoA:cholesterol acyltransferase (ACAT),the enzyme responsible for the esterification of dietary cholesterol.Such agents may decrease the absorption of dietary cholesterol andtherefore provide a therapy for individuals with hypercholesterolemia.

INFORMATION DISCLOSURE STATEMENT

Swiss Patent 407,978 (Chem. Pharm. Fabrik.), published Sep. 30, 1966(Derwent 24231), describes compounds of the following formula ashypoglycemic agents:

    RSO.sub.2 NHCONHR

wherein R is alkyl, cycloalkyl, alkylcycloalkyl optionally substitutedby one or more halogen or CNS groups or alkyl substituted phenyl inwhich at least one of the substituents is halogen or CNS groups and thealkyl group contains 3 to 8 carbon atoms.

The following specific compounds are disclosed:

    C.sub.4 H.sub.9 --NHCONHSO.sub.2 (CH.sub.2).sub.3 CH.sub.2 Cl; ##STR2##

French Patent 2,501, 681 (Ciba-Geigy), published Jul. 15, 1981,describes the following compounds as agrochemical bioregulators(microbicides, bactericides, and fungicides): ##STR3## wherein R₁ isalkylC₁₋₄, alkoxyC₁₋₄, or halogen; R₂ is hydrogen, alkylC₁₋₃,alkoxyC₁₋₄, or halogen;

R₃ is hydrogen, alkylC₁₋₃, or halogen;

R₄ is hydrogen or methyl; provided the total number of carbons in theR₁, R₂, R₃, and R₄ substituents does not total more than 8;

X is --CH₂ -- or ##STR4## R₅ is --COOR', COSR', or ##STR5## wherein R',R", and R'" are independently methyl or ethyl; ##STR6## and R⁶ is

(a) alkylC₁₋₆ optionally substituted with halogen or alkoxyC₁₋₃ ; oralkenyl C₂₋₆ optionally substituted with halogen; or alkynylC₃₋₆ orcycloalkyl C₃₋₆ ;

(b) phenyl or benzyl optionally substituted with halogen, nitro,alkylC₁₋₃, or alkoxyC₁₋₃ ; or

(c) a 5- or 6-member heterocyclic which is saturated, unsaturated, orpartially saturated optionally substituted with alkylC₁₃, or halogen andcontains at least one oxygen atom.

The compounds of this reference which are most closely relatedstructurally to the present invention are the following:

    ______________________________________                                        1  STR7##                                                                     R.sub.2                                                                              R.sub.3  Z.sub.1   Y--R.sub.6                                          ______________________________________                                        CH.sub.3                                                                             3-CH.sub.3                                                                             --OCH.sub.3                                                                             --SO.sub.2 CH.sub.3                                   --Cl H --OCH.sub.3 --SO.sub.2 CH.sub.3                                         - --Cl H --OCH.sub.3                                                                                 2  STR8##                                              - --CH.sub.3 3-CH.sub.3 --OC.sub.2 H.sub.5 --SO.sub.2 CH.sub.3                                         - --CH.sub.3 3-CH.sub.3 --OCH.sub.3                                         3  STR9##                                              - --C.sub.2 H.sub.5 H --SCH.sub.3 --SO.sub.2 CH.sub.2 CH.sub.2 Cl                                      - --CH.sub.3 3-CH.sub.3 --OCH.sub.3                                         4  STR10##                                             - --CH.sub.3 H --OCH.sub.3 --SO.sub.2 CH.sub.2 CH.sub.2 Cl                   --CH.sub.3                                                                   3-Br --OCH.sub.3 --SO.sub.2 CH.sub.3                                           --C.sub.2 H.sub.5 H --SCH.sub.3 --SO.sub.2 CHClCH.sub.2 Cl                    --C.sub.2 H.sub.5 H --N(CH.sub.3).sub.2 --SO.sub.2 CH.sub.3                   --C.sub.2 H.sub.5 4-Br --OCH.sub.3 --SO.sub.2 CH.sub.3                        --CH.sub.3 4-Br --OCH.sub.3 --SO.sub.2 C.sub.2 H.sub.5                        --C.sub.2 H.sub.5 H --OCH.sub.3 --SO.sub.2 CH.sub.3                           --C.sub.2 H.sub.5 H --N(C.sub.2 H.sub.5).sub.2 --SO.sub.2 CH.sub.3                                      - --C.sub.2 H.sub.5 4-Br --OCH.sub.3                                        2  STR11##                                             - --C.sub.2 H.sub.5 H --OCH.sub.3 --SO.sub.2 C.sub.2 H.sub.5                  - --C.sub.2 H.sub.5 H --OCH.sub.3                                                                    3  STR12##                                             - --C.sub.2 H.sub.5 H --OCH.sub.3                                                                    4  STR13##                                             - --C.sub.2 H.sub.5 H --N(CH.sub.3).sub.2 --SO.sub.2 C.sub.2 H.sub.5                                   - --C.sub.2 H.sub.5 H --OCH.sub.3                                           2  STR14##                                             - --CH.sub.3 H --OCH.sub.3 --SO.sub.2 CHClCH.sub.2 Cl                        --CH.sub.3 H --OCH.sub.3 --SO.sub.2 CH.sub.3                                  --CH.sub.3 H --OCH.sub.3 --SO.sub.2 C.sub.2 H.sub.5                            - --CH.sub.3 H --OCH.sub.3                                                                           3  STR15##                                             - --CH.sub.3 H --OCH.sub.3                                                                           4  STR16##                                             - --CH.sub.3 H --OCH.sub.3                                                                           2  STR17##                                             - --CH.sub.3 4-CH.sub.3 --OCH.sub.3 --SO.sub.2 C.sub.2 H.sub.5                                         - --CH.sub.3 4-CH.sub.3 --OCH.sub.3                                         2  STR18##                                             - --C.sub.2 H.sub.5 H --OCH.sub.3 --SO.sub.2 CHClCH.sub.2 Cl                  - --CH.sub.3 H --SCH.sub.3                                                                           2  STR19##                                          5  STR20##                                                                    ______________________________________                                          R.sub.1  R.sub.2  Z.sub.1 Y--R.sub.6                                        ______________________________________                                          C.sub.2 H.sub.5 C.sub.2 H.sub.5 --N(CH.sub.3).sub.2 --SO.sub.2 C.sub.2                                  H.sub.5                                             t-C.sub.4 H.sub.9 H --N(CH.sub.3).sub.2 --SO.sub.2 CH.sub.3                   CH.sub.3 --OCH.sub.3 --N(C.sub.2 H.sub.5).sub.2 --SO.sub.2 CH.sub.3                                      i-OC.sub.3 H.sub.7 H --N(CH.sub.3).sub.2                                     --SO.sub.2 CH.sub.3                                 Cl Cl --N(CH.sub.3).sub.2 --SO.sub.2 CH.sub.3                                 CH.sub.3 C.sub.2 H.sub.5 --N(C.sub.2 H.sub.5).sub.2 --SO.sub.2 C.sub.2                                  H.sub.5                                             C.sub.2 H.sub.5 --C.sub.2 H.sub.5 --N(CH.sub.3).sub.2 --SO.sub.2                                        CH.sub.2 CH.sub.2 Cl                                i-OC.sub.3 H.sub.7 H --N(C.sub.2 H.sub.5).sub.2 --SO.sub.2 C.sub.2                                      H.sub.5                                             CH.sub.3 --OCH.sub.3 --N(C.sub.2 H.sub.5).sub.2 --SO.sub.2 C.sub.2                                      H.sub.5                                             z-C.sub.4 H.sub.9 H --N(C.sub.2 H.sub.5).sub.2 --SO.sub.2 C.sub.2                                       H.sub.5                                             CH.sub.3 --C.sub.2 H.sub.5 --N(C.sub.2 H.sub.5).sub.2 --SO.sub.2                                        CH.sub.3                                          6  STR21##                                                                    ______________________________________                                    

SUMMARY OF THE INVENTION

The present invention provides pharmaceutically useful compounds of thefollowing general Formula I: ##STR22## wherein X is oxygen or --NH--;wherein Ar is

(a) phenyl which is unsubstituted or is substituted with from one tothree substituents selected from:

alkyl having from 1 to 4 carbon atoms and which is straight or branched,

alkoxy having from 1 to 3 carbon atoms and which is straight orbranched,

hydroxy,

fluorine,

chlorine,

bromine,

nitro,

cyano,

trifluoromethyl,

--COOH,

--COOalkyl wherein alkyl has from 1 to 4 carbon atoms and which isstraight or branched,

--(CH₂)_(m) NR₃ R₄ wherein m is zero or one, and each of R₃ and R₄ ishydrogen or a straight or branched alkyl group having 1 to 4 carbonatoms;

(b) 1- or 2-naphthyl which is unsubstituted or substituted with one tothree substituents selected from:

alkyl having from 1 to 4 carbon atoms and which is straight or branched,

alkoxy having from 1 to 3 carbon atoms and which is straight orbranched,

hydroxy,

fluorine,

chlorine,

bromine,

nitro,

cyano,

trifluoromethyl,

--COOH,

--COOalkyl wherein alkyl has from 1 to 4 carbon atoms and is straight orbranched,

--(CH₂)_(m) NR₃ R₄ wherein m, R₃, and R₄ have the meanings definedabove;

wherein R₁ is hydrogen, lower alkyl having from 1 to 4 carbon atoms orbenzyl;

wherein R₂ is ##STR23## wherein each of R₅ and R₆ is hydrogen, methyl,ethyl, phenyl, phenyl substituted with straight or branched lower alkylhaving from 1 to 4 carbon atoms, straight or branched lower alkoxyhaving from 1 to 4 carbon atoms, chlorine, fluorine or bromine, or R₅and R₆ together with the carbon atom to which they are attached form acyclic group having from 3 to 8 carbon atoms; and R₇ is a straight orbranched alkyl group having from 4 to 16 carbon atoms; andpharmaceutically acceptable salts thereof.

The compounds of Formula I are useful in treating atherosclerosis.

DETAILED DESCRIPTION OF INVENTION

Pharmaceutically acceptable salts of the compounds of Formula I are alsoincluded as a part of the present invention.

The base salts may be generated from compounds of Formula I by reactionof an appropriate compound of the latter with one equivalent of asuitable nontoxic, pharmaceutically acceptable base followed byevaporation of the solvent employed for the reaction andrecrystallization of the salt, if required. The compounds of Formula Imay be recovered from the base salt by reaction of the salt with anaqueous solution of a suitable acid such as hydrobromic, hydrochloric,or acetic acid.

Suitable bases for forming base salts of the compounds of this inventioninclude amines such as triethylamine or dibutylamine, or alkali metalbases and alkaline earth metal bases. Preferred alkali metal hydroxidesand alkaline earth metal hydroxides as salt formers are the hydroxidesof lithium, sodium, potassium, magnesium, or calcium. The class of basessuitable for the formation of nontoxic, pharmaceutically acceptablesalts is well known to practitioners of the pharmaceutical formulationarts. See, for example, Stephen N. Berge, et al, J. Pharm. Sci. 66, 1-19(1977).

Suitable acids for forming acid salts of the compounds of Formula Icontaining a basic group include, but are not necessarily limited toacetic, benzoic, benzenesulfonic, hydrobromic, hydrochloric, citric,fumaric, gluconic, glucuronic, glutamic, lactic, malic, maleic,methanesulfonic, pamoic, salicylic, stearic, succinic, sulfuric, andtartaric acids. The acid addition salts are formed by procedures wellknown in the art.

Certain compounds of the present invention may also exist in differentstereoisomeric forms by virtue of the presence of asymmetric centers inthe compound. The present invention contemplates all stereoisomers maybe obtained, if desired, by methods known in the art as, for example,the separation of stereoisomers in chiral chromatographic columns.

Further, the compounds of this invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like. In general, the solvated forms areconsidered equivalent to the unsolvated forms for the purposes of thisinvention.

Illustrative examples of straight or branched alkyl groups having from 4to 16 carbon atoms include n-butyl, iso-butyl, tert-butyl, n-pentyl,isopentyl, n-hexyl, n-heptyl, n-octyl, n-undecyl, n-dodecyl,n-hexadecyl, 8,8-dimethyldodecyl, 2-tetradecyl groups, and6-methylundecyl.

Preferred compounds of the present invention are those wherein X is NHand Ar is phenyl or substituted phenyl with substituted phenyl beingmore preferred. The most preferred compounds of this invention are thosewherein Ar is phenyl disubstituted on the 2,6-positions ortrisubstituted on the 2,4,6-positions and wherein each of R₅ and R₆ ishydrogen with compounds wherein Ar is 2,6-diisopropylphenyl beingespecially preferred.

Pharmaceutical compositions containing the compounds of Formula I andmethods of using the compounds of Formula I to lower blood cholesterollevels are also included in the scope of the present invention.

As shown by the data presented below in Table 1, the compounds of thepresent invention are potent inhibitors of the enzymeacyl-CoA:cholesterol acyltransferase (ACAT), and are thus effective ininhibiting the esterification and transport of cholesterol across theintestinal cell wall. The compounds of the present invention are thususeful in pharmaceutical formulations for the treatment ofhypercholesterolemia or atherosclerosis.

The ability of representative compounds of the present invention toinhibit ACAT was measured using an in vitro test more fully described inF. J. Field and R. G. Salone, Biochemica et Biophysica 712:557-570(1982). The test assesses the ability of a test compound to inhibit theacylation of cholesterol by oleic acid by measuring the amount ofradiolabeled cholesterol oleate formed from radiolabeled oleic acid in atissue preparation containing rabbit intestinal microsomes.

The data appear in Table 1 where they are expressed as IC₅₀ values;i.e., the concentration of test compound required to inhibit theactivity of the enzyme by 50%.

                  TABLE 1                                                         ______________________________________                                                      IAI                                                               Example IC.sub.50 (μM)                                                   ______________________________________                                               1      1.02                                                              2 0.83                                                                        3 >5                                                                          4 0.51                                                                        5 >5                                                                          6 1.19                                                                        7 1.27                                                                        8 13                                                                          10  5.0                                                                       11  0.086                                                                     14  2.0                                                                       15  9.2                                                                     ______________________________________                                    

In one in vivo screen designated APCC, male Sprague-Dawley rats (200 to225 g) were randomly divided into treatment groups and dosed at 4 PMwith either vehicle (CMC/Tween) or suspensions of compounds in vehicle.The normal chow diet was then replaced with a high fat, high cholesteroldiet with 0.5% cholic acid. The rats consumed this diet ad libitumduring the night and were sacrificed at 8 AM to obtain blood samples forcholesterol analysis using standard procedures. Statistical differencesbetween mean cholesterol values for the same vehicle were determinedusing analysis of variance followed by Fisher's least significant test.The results of this trial for representative compounds of the presentinvention appear in Table 2. The compounds were dosed at 30 mg/kg unlessotherwise noted.

                  TABLE 2                                                         ______________________________________                                        Example      APCC (% ΔTC)                                               ______________________________________                                        1            -76                                                                2 -56                                                                         3 -34                                                                         6 -63                                                                         7 -64                                                                         8 -31                                                                         10  -14                                                                       11  -49                                                                       14  -72                                                                       15  -75                                                                     ______________________________________                                    

In therapeutic use as agents for treating hypercholesterolemia oratherosclerosis, the compounds of Formula I or pharmaceuticallyacceptable salts thereof are administered to the patient at dosagelevels of from 250 to 3000 mg per day. For a normal human adult ofapproximately 70 kg of body weight, this translates into a dosage offrom 5 to 40 mg/kg of body weight per day. The specific dosagesemployed, however, may be varied depending upon the requirements of thepatient, the severity of the condition being treated, and the activityof the compound being employed. The determination of optimum dosages fora particular situation is within the skill of the art.

For preparing the pharmaceutical compositions from the compounds of thisinvention, inert, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,dispersible granules, capsules, and cachets.

A solid carrier can be one or more substances which may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, or tablet disintegrating agents; it can also be anencapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component. In tablets, the activecomponent is mixed with the carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired.

Powders and tablets preferably contain between about 5% to about 70% byweight of the active ingredient. Suitable carriers are magnesiumdicarbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin,starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, alow-melting wax, cocoa butter, and the like.

The term "preparation" is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component (with or without carriers) issurrounded by a carrier, which is thus in association with it. In asimilar manner cachets are also included.

Tablets, powders, cachets, and capsules can be used as solid dosageforms suitable for oral administration.

Liquid form preparations include solutions, suspensions, or emulsionssuitable for oral administration. Aqueous solutions for oraladministration can be prepared by dissolving the active compound inwater and adding suitable flavorants, coloring agents, stabilizers, andthickening agents as desired. Aqueous suspensions for oral use can bemade by dispersing the finely divided active component in water togetherwith a viscous material such as natural or synthetic gums, resins,methyl cellulose, sodium carboxymethylcellulose, and other suspendingagents known to the pharmaceutical formulation art.

Preferably, the pharmaceutical preparation is in unit dosage form. Insuch form, the preparation is divided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation containing discrete quantities of thepreparation, for example, packeted tablets, capsules, and powders invials or ampoules. The unit dosage form can also be a capsule, cachet,or tablet itself, or it can be the appropriate number of these packagedforms.

The compounds of the present invention can be prepared by various means.Overall, the means by which the compounds of Formula I are prepared isset forth in Chart I hereof. In Chart I X, R₂ and Ar have the meaningsdefined in Formula I, and R₈ is lower alkyl having from 1 to 4 carbonatoms or benzyl. Typically, the sulfonyl chloride (1) is reacted withammonium hydroxide in methanol or ethanol to give the sulfonamide (2).The sulfonamide (2) is reacted with an appropriate arylisocyanate,(ArNCO) or aryl chloroformate (ArOCOCl), in dimethylformamide and sodiumhydride to give the sulfonyl urea (3) or sulfonyl carbamate (5),respectively, which can be alkylated using an appropriate benzyl halideor alkylhalide, R₈ halo, wherein R₈ is benzyl or lower alkylC₁₋₄ andhalo is chlorine, bromine, or iodine in acetonitrile and1,8-diazabicyclo[5.4.0]undec-7-ene to give compounds (4) and (6). Thebase salts of the sulfonyl ureas (3) or the sulfonyl carbamates (5) areformed by reacting these compounds with an appropriate base.

The sulfonyl chlorides (1) are commercially available or can be preparedby well known procedures as generally outlined in Chart II hereof inScheme I.

In Scheme I, X is chlorine, bromine, or iodine, and R₉ is typically astraight chain alkyl group having from 5 to 17 carbon atoms. Thealiphatic halide, R₉ X, is reacted with sodium sulfonite in aqueousethanol at reflux to give the aliphatic sodium sulfonate, R₉ SO₃ Na,which is treated with phosphorous oxychloride or phosphorouspentachloride to give the sulfonyl chloride derivative R₉ SO₂ Cl.

In Scheme II of Chart II there is set forth a means for obtaining thesulfonamides (2) of Chart I. In Scheme II R₁₀ and R₁₁ can be hydrogen,methyl, ethyl, or phenyl or R₁₀ and R₁₁ can be taken together with thecarbon to which they are attached to form a cycloalkyl group having from3 to 8 carbon atoms and R can be a straight or branched alkyl grouphaving from 4 to 16 carbon atoms. The sulfonyl chloride (a) is treatedwith t-butylamine in tetrahydrofuran to give the N-t-butylsulfonamidederivative (b) which is treated with two equivalents of n-butyllithiumaccording to the procedure set forth in J. Org. Chem. 49:1700-1703(1984), followed by treatment with an alkylating agent RX wherein R isas defined above and X is bromine or iodine to give compounds (c) whichare treated with trifluoroacetic acid to give the sulfonamides (d).

The following specific examples will further illustrate the synthesis ofcompounds of the present invention.

EXAMPLE 1

N-[2,6-Bis(1-methylethyl)phenyl]-N'-(2-pentadecylsulfonyl)urea

(a) n-BuLi (1.6M, 32 mL) was added dropwise to a 0° C. solution ofN-t-butylethanesulfonamide (4.0 g, 24 mmoles) in anhydrous THF (80 mL)under dry N₂. The solution was stirred for 30 minutes at 0° C. thenwarmed to room temperature for 30 minutes. It was then cooled back to 0°C. and a solution of 1-bromotridecane (6.4 mL, 25 mmoles) in 10 mLanhydrous THF (distilled from Na--Ph₂ CO) was added dropwise. Thesolution was allowed to warm to room temperature overnight, quenched byaddition of 1N HCl (60 mL), and partitioned between ethyl acetate andbrine. The organic layer was dried, filtered, and concentrated to anoil, which was dissolved in 40 mL of CF₃ CO₂ H and stirred overnight atroom temperature. It was then concentrated and the solid residuerecrystallized from iPr₂ O to afford 4.8 g (68%) of2-pentadecylsulfonamide as a light brown (almond) powder. (b) A solutionof 2-pentadecylsulfonamide (2.91 g, 10 mmoles) in DMF (40 mL dried over3Å sieves) was added dropwise to a stirred, 0° C. suspension of NaH (0.5g, 21 mmoles of hexane washed) in 10 mL dry DMF. The mixture was stirred30 minutes at 0° C., then warmed to room temperature for 3 hours. It wasthen cooled back to 0° C. and a solution of2,6-diisopropylphenylisocyanate (2.14 mL, 10 mmoles) in 10 mL DMF wasadded dropwise. The mixture was allowed to warm to room temperatureovernight, cooled to 0° C., and quenched by dropwise addition of 1N HCl(60 mL). The mixture was partitioned between EtOAc (300 mL) and H₂ O(100 mL). The organic layer was further washed with brine, dried,filtered, and evaporated to provide an oil which was flashchromatographed (silica gel, 4:1 hexane-EtOAc) to produce 3 g of an oilwhich solidified on standing (m.p. 65-75° C.).

EXAMPLE 2

N-[2,6-Bis(1-methylethyl)phenyl]-N'-(tetradecylsulfonyl)urea

(a) Sodium, 1-tetradecane sulfonate

A mixture of 1-bromotetradecane (59.5 g, 200 mmoles) and Na₂ SO₃ (27.86g, 221 mmoles) was stirred and heated in 200 mL of 1:1 H₂ O-EtOH atreflux while stirring vigorously. The mixture was refluxed overnight,cooled to 0° C., and the precipitate isolated by suction filtration anddried at 70° C. under vacuo. Isolated 22.2 g of colorless solid,m.p. >235° C.

(b) 1-Tetradecanesulfonamide

A mixture of POCl₃ (19 mL, ˜200 mmoles) and sodium,1-tetradecanesulfonate (34.8 g, 115 mmoles) was stirred and heated at180° C. for 18 hours. After cooling to room temperature, the mixture wasdigested with ice water, then partitioned between EtOAc and water (500mL each). The aqueous layer was further extracted with EtOAc. Thecombined EtOAc extracts were washed with brine (200 mL), dried,filtered, and evaporated. The residue was combined with 200 mLconcentrated NH₄ OH and heated on a steam bath until gas evolution wascomplete (˜30 minutes) with swirling. The mixture was then concentratedand partitioned between ethyl acetate (EtOAc) and water. The aqueouslayer was exhaustively extracted with EtOAc. The EtOAc extracts werewashed with brine and dried. Recrystallization of the solid whichremained after filtration and concentration from EtOAc afforded 10.4 gof 1-tetradecylsulfonamide, m.p. 92-93° C.

(c) A solution of 1-tetradecylsulfonamide (9.0 g, 32.4 mmoles) in DMF(90 mL) was added dropwise to a stirred suspension of NaH (1.63 g, 68mmoles) in 30 mL of DMF. The solution was stirred 60 minutes, then2,6-diisopropylphenyl isocyanate (7.0 mL, 33 mmoles) was added dropwise.The mixture was stirred overnight at room temperature, then quenched bydropwise addition of 1M HCl. The mixture was then partitioned between H₂O and ethyl acetate (500 mL each). The aqueous layer was furtherextracted with ethyl acetate. The combined ethyl acetate extracts werediluted with hexane (100 mL) and then washed exhaustively with H₂ O. Theorganic extracts were dried, filtered, and concentrated to a solidresidue, which was triturated with ether and the solid isolated bysuction filtration and dried. Isolated 9.70 g of solid, m.p. 135-137° C.

EXAMPLE 3

N-[2,6-Bis(1-methylethyl)phenyl]-N'-methyl-N'-(tetradecylsulfonyl)urea

CH₃ I (0.15 mL, 2.3 mmoles) was added dropwise to a room temperaturesolution of N-[2,6-bis(1-methylethyl)phenyl]-N'-(tetradecylsulfonyl)urea(1.0 g, 2.08 mmoles) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.34 mL,2.3 mmoles), stirring in 10 mL of CH₃ CN. The solution was stirredovernight at room temperature, diluted with EtOAc, washed with 1M HCl,H₂ O, brine, and dried (MgSO₄). Filtration and evaporation afforded anoil which was flash chromatographed (silica gel, 10:1 hexane-ethylacetate) to provide 800 mg of a colorless oil.

Anal. Calcd. for C₂₈ R₅₀ N₂ O₃ S: C, 67.97; H, 10.19; N, 5.66; S, 6.48.

Found: C, 68.58; H, 10.21; N, 5.83; S, 6.14.

EXAMPLE 4

N-[2,6-Bis(1-methylethyl)phenyl]-N'-phenylmethyl-N'-(tetradecylsulfonyl)ure

Benzyl bromide (0.2 mL, 1.68 mmoles) was added to a stirred, roomtemperature solution ofN-[2,6-bis(1-methylethyl)phenyl]-N'-(tetradecylsulfonyl)urea (0.5 g, 1mmole) and DBU (0.16 mL, 1.1 mmoles) in 10 mL of CH₃ CN. The mixture wasallowed to stir overnight at room temperature, poured into ether (200mL), and washed with H₂ O (50 mL), 1N HCl (50 mL), brine (50 mL), anddried (MgSO₄). The residue that remained after filtration andconcentration was flash chromatographed on silica gel (25:1 v/v,hexane-ethyl acetate) to afford 300 mg of an oil which solidified onstanding, m.p. 50-53° C.

When in the procedure of Example 2, step (a) an appropriate amount of1-bromooctane, 1-bromododecane, 1-bromohexadecane, 1-bromodecane, or1-bromotridecane is substituted for 1-bromotetradecane and the generalprocedure of step (a) is followed, the following salts were obtained:

sodium, 1-octane sulfonate,

sodium, 1-dodecane sulfonate,

sodium 1-hexadecane sulfonate,

sodium, 1-decane sulfonate, and

sodium, 1-tridecane sulfonate.

When in the procedure of Example 2, step (b) each of the above-obtainedsalts is substituted for sodium, 1-tetradecane sulfonate and the generalprocedure of step (b) is followed, the following respective compoundswere obtained:

1-octanesulfonamide,

1-dodecanesulfonamide,

1-hexadecanesulfonamide,

1-decanesulfonamide, and

1-tridecanesulfonamide.

When in the procedure of Example 2, step (c) each of the above-obtainedsulfonamides is substituted for 1-tetradecanesulfonamide and the generalprocedure of step (c) is followed, the following respective products(Examples 6-9) were obtained:

EXAMPLE 5

N-[2,6-Bis(1-methylethyl)phenyl]-N'-(octylsulfonyl)urea, m.p. 133-136°C.

EXAMPLE 6

N-[2,6-Bis(1-methylethyl)phenyl]-N'-(dodecylsulfonyl)-urea, m.p.125-127° C.

EXAMPLE 7

N-[2,6-Bis(1-methylethyl)phenyl]-N'-(hexadecylsulfonyl)urea, m.p.123-126° C.

EXAMPLE 8

N-[2,6-Bis(1-methylethyl)phenyl]-N'-(decylsulfonyl)urea, m.p. 152-154°C.

EXAMPLE 9

N-[2,6-Bis(1-methylethyl)phenyl]-N'-(tridecylsulfonyl)urea, m.p.121-123° C.

EXAMPLE 10

N-(2,4-Difluorophenyl)-N'-(tetradecylsulfonyl)urea

When in the procedure of Example 2, part (c) an appropriate amount of2,6-difluorophenyl isocyanate is substituted for 2,6-diisopropylphenylisocyanate and the general procedure of part (c) is followed, the titlecompound is obtained, m.p. 88-92° C.

EXAMPLE 11

N-[2,6-Bis(1-methylethyl)phenyl]-N'-methyl-N'-(dodecylsulfonyl)urea

When in the procedure of Example 3 an appropriate amount of the productof Example 7 was substituted forN-[2,6-bis(1-methylethyl)phenyl]-N'-(tetradecylsulfonyl)urea and theprocedure of Example 3 was followed, the title compound was obtained asan oil.

EXAMPLE 12

N-(2,4,6-Trimethoxyphenyl)-N'-(hexadecylsulfonyl)urea

When in the procedure of Example 2, part (c) an appropriate amount of1-hexadecanesulfonamide is substituted for 1-tetradecanesulfonamide, andan appropriate amount of 2,4,6-trimethoxyphenylisocyanate is substitutedfor 2,6-diisopropylphenylisocyanate and the general procedure of Example2, part (c) is followed, the title compound was obtained.

EXAMPLE 13

N-[2,6-Bis(1-methylethyl)phenyl]-N'-(2-methyl-2-pentadecylsulfonyl)urea

When in the procedure of Example 1 (a) an appropriate amount ofN-t-butyl isopropylsulfonamide was substituted for N-t-butylethanesulfonamide and the general procedure of Example 1(a) wasfollowed, 2-methyl-2-pentadecylsulfonamide was obtained, and when anappropriate amount of said sulfonamide was substituted for2-pentadecylsulfonamide in the procedure of Example 1(b) and the generalprocedure of Example 1(b) was followed, the title compound was obtained.

EXAMPLE 14

N-[2,6-Bis(1-methylethyl)phenyl]-N'-(1-phenyl-1-tetradecylsulfonyl)urea

When in the procedure of Example 1(a) an appropriate amount of N-t-butylbenzylsulfonamide is substituted for N-t-butylethanesulfonamide and thegeneral procedure of Example 1(a) and 1(b) was followed, the titlecompound was obtained, m.p. 97-102° C.

EXAMPLE 15

N-[2,6-Bis(1-methylethyl)phenyl]-N'-(1-phenyl-1-nonylsulfonyl)urea

When in the procedure of Example 1(a) an appropriate amount of N-t-butylbenzylsulfonamide was substituted for N-t-butylethanesulfonamide and anappropriate amount of 1-bromononane was substituted for 1-bromotridecaneand the general procedure of Example 1(a) and 1(b) was followed, thetitle compound was obtained, m.p. 145-146° C.

EXAMPLE 16

N-[2,6-Bis(1-methylethyl)phenyl]-N'-(2-decylsulfonyl)urea

When in the procedure of Example 1(a) an appropriate amount of1-bromooctane was substituted for 1-bromotridecane and the generalprocedure of Example 1(a) and 1(b) was followed, the title compound wasobtained, CI MS M⁺ 424.

EXAMPLE 17

2,6-Bis(1-methylethyl)phenyl]-N'-(tetradecylsulfonyl)carbamate

When in the procedure of Example 2, part (c) an appropriate amount of[2,6-bis(1-methylethyl)phenyl]chloroformate (M. V. Zabik; R. D. Schuetz,J. Org. Chem. 32, 300-7 (1967)) is substituted for 2,6-diisopropylphenylisocyanate and the general procedure of part (c) is followed, the titlecompound is obtained. ##STR24##

We claim:
 1. A compound of the formula wherein X is --NH--;wherein Ar is(a) phenyl which is substituted by2,6 -bis(methylethyl),2,4,6-trimethoxy, or from one to three substituents selectedfrom:hydroxy, nitro, --COOH, --COOalkyl wherein alkyl has from 1 to 4carbon atoms and which is straight or branched, and --(CH₂)_(m) NR₃ R₄wherein m is zero or one, and each of R₃ and R₄ is hydrogen or astraight or branched alkyl group having 1 to 4 carbon atoms; or (b) 1-or 2-naphthyl which is unsubstituted or substituted with one to threesubstituents selected from:alkyl having from 1 to 4 carbon atoms andwhich is straight or branched, alkoxy having from 1 to 3 carbon atomsand which is straight or branched, hydroxy, fluorine, chlorine, bromine,nitro, cyano, trifluoromethyl, --COOH, --COOalkyl wherein alkyl has from1 to 4 carbon atoms and is straight or branched, --(CH₂)_(m) NR₃ R₄wherein m, R₃, and R₄ have the meanings defined above;wherein R₁ ishydrogen, lower alkyl having from 1 to 4 carbon atoms or benzyl; whereinR₂ is ##STR25## wherein each of R₅ and R₆ is hydrogen, methyl or ethyl,or R₅ and R₆ together with the carbon atom to which they are attachedform a cyclic group having from 3 to 8 carbon atoms; and R₇ is astraight or branched alkyl group having from 4 to 16 carbon atoms; andpharmaceutically acceptable salts thereof.
 2. A compound of claim 1wherein Ar is phenyl which is substituted by2,6 -bis(methylethyl),2,4,6-trimethoxy, or from one to three substituents selectedfrom:hydroxy; nitro; --COOH; --COOalkyl wherein alkyl has from 1 to 4carbon atoms and which is straight or branched; --(CH₂)_(m) NR₃ R₄wherein m is zero or one, and each of R₃ and R₄ is hydrogen or astraight or branched alkyl group having from 1 to 4 carbon atoms.
 3. Acompound of claim 2 wherein each of R₅ and R₆ is hydrogen.
 4. A compoundof claim 3 which isN-[2,6-bis(1-methylethyl)phenyl]-N'-(tetradecylsulfonyl)urea;N-[2,6-bis(1-methylethyl)phenyl]-N'-methyl-N'-(tetradecylsulfonyl)urea;N-[2,6-bis(1-methylethyl)phenyl]-N'-phenylmethyl-N'-(tetradecylsulfonyl)urea;N-[2,6-bis(1-methylethyl)phenyl]-N'-(octylsulfonyl)urea;N-[2,6-bis(1-methylethyl)phenyl]-N'-(dodecylsulfonyl)urea;N-[2,6-bis(1-methylethyl)phenyl]-N'-(hexadecylsulfonyl)urea;N-[2,6-bis(1-methylethyl)phenyl]-N'-methyl-N'-(dodecylsulfonyl)urea;N-[2,6-bis(1-methylethyl)phenyl]-N'-(decylsulfonyl)urea;N-[2,6-Bis(1-methylethyl)phenyl]-N'-(tridecylsulfonyl)urea; orN-[2,4,6-trimethoxyphenyl]-N'-(hexadecylsulfonyl)urea.
 5. A compound ofclaim 2 wherein each of R₅ and R₆ is methyl or ethyl.
 6. A compound ofclaim 5 whichisN-[2,6-bis(1-methylethyl)phenyl]-N'-(2-pentadecylsulfonyl)urea;N-[2,6-bis(1-methylethyl)phenyl]-N'-(2-methyl-2-pentadecylsulfonyl)urea; and N-[2,6-bis(1 -methylethyl)phenyl]-N'-(2-decylsulfonyl) urea.7. A compound of claim 1 wherein Ar is phenyl disubstituted on the2,6-positions with isopropyl groups or phenyl trisubstituted on the 2-,4-, 6-positions with methoxy and each of R₅ and R₆ is hydrogen.
 8. Apharmaceutical composition which comprises a compound of claim 1 incombination with a pharmaceutically acceptable carrier.